This invention relates to 2-pyrimidineamine derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
Protein kinases participate in the signalling events which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these kinases fall into two groups; those which preferentially phosphorylate serine and/or threonine residues and those which preferentially phosphorylate tyrosine residues [Hanks, S K, Hunter T, FASEB. J. 9, 576-596 (1995)]. The serine/threonine kinases include for example, protein kinase C isoforms [Newton A C, J. Biol. Chem. 270, 28495-28498 (1995)] and a group of cyclin-dependent kinases such as cdc2 [Pines J, Trends in Biochemical Sciences 18, 195-197 (1995)]. The tyrosine kinases include membrane-spanning growth factor receptors such as the epidermal growth factor receptor [Iwashita S and Kobayashi M. Cellular Signalling 4, 123-132 (1992)], and cytosolic non-receptor kinases such as p56Ick p59fyn ZAP-70 and csk kinases [Chan C et al Ann. Rev. Immunol. 12, 555-592 (1994)].
Inappropriately high protein kinase activity has been implicated in many diseases resulting from abnormal cellular function. This might arise either directly or indirectly, for example by failure of the proper control mechanisms for the kinase, related for example to mutation, overexpression or inappropriate activation of the enzyme; or by over- or underproduction of cytokines or growth factors also participating in the transduction of signal upstream or downstream of the kinase. In all of these instances, selective inhibition of the action of the kinase might be expected to have a beneficial effect.
We have now found a series of 2-pyrimidineamine derivatives which are potent and selective inhibitors of the protein tyrosine kinases ZAP-70 and syk. The ZAP-70 kinase is involved in the transduction of signals from the T-cell receptor and thus in the activation of T-cells during the immune response. The closely related kinase syk is involved in signalling from the B-cell receptor and thus in the activation of B-cells during the immune response [van Oers N S, Weiss A, Seminars in Immunology, 7, 227-236, (1995) and is also involved in signalling from the Fc epsilon RI, the high-affinity IgE receptor present on mast cells [Zhang J. et al, J. Exp. Med. 184, 71-79 (1996)] and in the survival of eosinophils mediated by IL5 and GM-CSF [Yousefi S, et al J. Exp. Med. 183, 1407-1414, (1996)]. Syk is further involved in the activation of platelets stimulated via the low-affinity IgG receptor (Fc gamma-RIIA) or stimulated by collagen [Yanaga F, et al, Biochem. J. 311, (Pt. 2) 471-478, (1995)].
The compounds of the invention are thus of use in the prophylaxis and treatment of immune diseases (including autoimmune diseases and transplant rejection), allergic diseases involving mast cells or eosinophils, and diseases involving inappropriate platelet activation.
Thus, according to one aspect of the invention, we provide a compound of formula (1): 
wherein
Ar is an optionally substituted aromatic group;
R2 is a hydrogen or halogen atom or a group xe2x80x94X1xe2x80x94R2a where X1 is a direct bond or a linker atom or group, and R2a is an optionally substituted straight or branched chain alkyl, alkenyl or alkynyl group;
R3 is an optionally substituted heterocycloalkyl group;
and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that in the compounds of formula (1) the pyrimidine and R3 groups may be attached to any ring carbon atom of the pyridyl group, provided always that they are not both attached to the same carbon atom.
The group R2 in compounds according to the invention may be for example a hydrogen or halogen atom such as a fluorine, chlorine, bromine or iodine atom, or a group xe2x80x94X1xe2x80x94R2a where X1 is a direct bond or linker atom or group, and R2a is an optionally substituted straight or branched chain alkyl, alkenyl or alkynyl group.
Linker atoms represented by X1 when present in compounds of formula (1) include xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms. When X1 is a linker group it may be for example a xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(R7)xe2x80x94[where R7 is a hydrogen atom or a C1-6 alkyl, e.g. methyl or ethyl, group], xe2x80x94CON(R7)xe2x80x94, xe2x80x94OC(O)N(R7)xe2x80x94, xe2x80x94CSN(R7)xe2x80x94, xe2x80x94N(R7)COxe2x80x94, xe2x80x94N(R7)C(O)Oxe2x80x94, xe2x80x94N(R7)CSxe2x80x94, xe2x80x94SON(R7), xe2x80x94SO2N(R7), xe2x80x94N(R7)SO2xe2x80x94, xe2x80x94N(R7)CON(R7)xe2x80x94, xe2x80x94N(R7)CSN(R7)xe2x80x94, xe2x80x94N(R7)SON(R7)xe2x80x94 or xe2x80x94N(R7)SO2N(R7) group.
When R2a is present in compounds of the invention it may be for example an optionally substituted straight or branched chain C1-6 alkyl, e.g. C1-3 alkyl, C2-6 alkenyl e.g. C2-4 alkenyl or C2-6 alkynyl e.g. C2-4 alkynyl group. Particular examples of such groups include optionally substituted xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94(CH2)2CH3, xe2x80x94CH(CH3)2, xe2x80x94(CH2)3CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94C(CH3)3, xe2x80x94(CH2)4CH3, xe2x80x94(CH2)5CH3, xe2x80x94CHCH2, xe2x80x94CHCHCH3, xe2x80x94CH2CHCH2, xe2x80x94CHCHCH2CH3, xe2x80x94CH2CHCHCH3, xe2x80x94(CH2)2CHCH2, xe2x80x94CCH, xe2x80x94CCCH3, xe2x80x94CH2CCH, xe2x80x94CCCH2CH3, xe2x80x94CH2CCCH3 or xe2x80x94(CH2)2CCH groups. The optional substituents which may be present on these groups include one, two, three or more substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl, C1-6 alkoxy, e.g. methoxy or ethoxy, thiol, C1-6 alkylthio, e.g. methylthio or ethylthio, amino C1-6 alkylamino, e.g. methylamino or ethylamino, or C1-6 dialkylamino, e.g. dimethylamino or diethylamino groups.
R3 in compounds of formula (1) may be for example an optionally substituted heteroC3-7heterocycloalkyl group containing one or two oxygen, or sulphur atoms or nitrogen containing groups. The heterocycloalkyl group may be attached to the remainder of the molecule of formula (1) through any of its carbon or, where present, nitrogen atoms as appropriate.
Where desired, any available nitrogen or carbon atom in R3 may be substituted by a group R4 where R4 is an optionally substituted straight or branched chain C1-6 alkyl, C1-6 alkoxy, hydroxyl (xe2x80x94OH), amino (xe2x80x94NH2), xe2x80x94NHR1a [where R1a is an optionally substituted straight or branched chain C1-6 alkyl group], xe2x80x94NR1aR1b [where R1b is as defined for R1a and may be the same as or different to R1a], carboxyl (xe2x80x94CO2H), esterified carboxyl (xe2x80x94CO2Alk1, where Alk1 is as defined below in connection with the group R5), xe2x80x94COR1a, carboxamido (xe2x80x94CONH2), thiocarboxamido (xe2x80x94CSNH2), xe2x80x94CONHR1a, xe2x80x94CONR1aR1b, xe2x80x94CSNHR1a, xe2x80x94CSNR1aR1b, xe2x80x94SO2R1a, xe2x80x94SO2NH2, xe2x80x94SO2NHR1a, xe2x80x94SO2NR1aR1b, imido, xe2x80x94SC(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94NHC(NH)R1a or an optionally substituted aromatic group. Additionally, any available carbon atom in the heterocycloalkyl group represented by R3 may be linked to an oxygen or sulphur atom to form a xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 group.
The heterocycloalkyl group R3 may contain one, two, three or more R4 substituents, the upper limit depending on the size of the ring and number of available carbon and/or nitrogen atoms.
When the substituent R4 is an optionally substituted alkyl or alkoxy group it may be for example an optionally substituted methyl, ethyl, prop-1-yl, prop-2-yl, methoxy or ethoxy group.
The groups R1a and R1b when present in the substituent R4 may be for example optionally substituted C1-3 alkyl groups such as optionally substituted methyl or ethyl groups.
Optional substituents which may be present on alkyl or alkoxy groups represented by R4, or in R1a and/or R1b groups, include one or two substituents selected from C1-6 alkoxy, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHR1a, xe2x80x94NR1aR1b, xe2x80x94CO2H, xe2x80x94CO2Alk1, xe2x80x94COR1a, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR1a, xe2x80x94CONR1aR1b, xe2x80x94CSNHR1a, xe2x80x94CSNR1aR1b, xe2x80x94SO2R1a, xe2x80x94SO2NH2, xe2x80x94SO2NHR1a, xe2x80x94SO2NR1aR1b, imido, xe2x80x94SC(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94NHC(NH)R1a or optionally substituted aromatic groups.
Optionally substituted aromatic groups represented by the substituent R4 or present as an optional substituent on a group R4, R1a or R1b include optionally substituted Ar1 groups where Ar1 is as defined herein for the group Ar. The optional substituents which may be present on the group Ar1 include those xe2x80x94R5 or -Alk(R5)m substituents described below in relation to the group Ar.
Particular examples of R3 groups include optionally substituted azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl or thiomorpholinyl groups. As explained above, these particular heterocycloalkyl groups may be attached to the remainder of the compound of the invention through any of their available ring carbon or nitrogen atoms.
Particular R4 substituents which may be present on R3 heterocycloalkyl groups include for example xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94(CH2)2CH3, xe2x80x94CH(CH3)2, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94O(CH2)2NH2, xe2x80x94O(CH2)2NHCH3, xe2x80x94O(CH2)2N(CH3)2, xe2x80x94CH2OH, xe2x80x94(CH2)2OH, xe2x80x94(CH2)3OH, xe2x80x94CH2NH2, xe2x80x94CH2NHCH3, xe2x80x94CH2N(CH3)2, xe2x80x94(CH2)2NH2, xe2x80x94(CH2)2NHCH3, xe2x80x94(CH2)2N(CH3)2, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94SO2NH2, xe2x80x94SO2 NHCH3, xe2x80x94SO2N(CH3)2, xe2x80x94(CH2)3-phthalimido, xe2x80x94Ar1 or xe2x80x94CH2Ar1 groups where in each instance Ar1 is an optionally substituted phenyl group.
Aromatic groups represented by Ar in compounds of formula (1) include for example optionally substituted monocyclic or bicyclic fused ring C6-12 aromatic groups, such as optionally substituted phenyl, 1- or 2-naphthyl, indanyl or indenyl groups.
Optional substituents which may be present on the aromatic group Ar include one, two, three or more substituents each represented by the atom or group R5 or -Alk(R5)m where R5 is a halogen atom, or an amino (xe2x80x94NH2), substituted amino, nitro, cyano, hydroxyl (xe2x80x94OH), substituted hydroxyl, formyl, carboxyl (xe2x80x94CO2H), esterified carboxyl, thiol (xe2x80x94SH), substituted thiol, xe2x80x94COR6 [where R6 is a -Alk(R5)m, aryl or heteroaryl group], xe2x80x94CSR6, xe2x80x94SO3H, xe2x80x94SO2R6, xe2x80x94SO2NH2, xe2x80x94SO2NHR6, SO2N[R6]2, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR6, xe2x80x94CSNHR6, xe2x80x94CON[R6]2, xe2x80x94CSN[R6]2, xe2x80x94NHSO2H, xe2x80x94NHSO2R6, xe2x80x94N[SO2R6]2, xe2x80x94NHSO2NH2, xe2x80x94NHSO2NHR6, xe2x80x94NHSO2N[R6]2, xe2x80x94NHCOR6, xe2x80x94NHCONH2, xe2x80x94NHCONHR6, xe2x80x94NHCON[R6]2, xe2x80x94NHCSR6, xe2x80x94NHC(O)OR6, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; Alk is a straight or branched C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain, optionally interrupted by one, two or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or groups selected from Sxe2x80x94(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R6)xe2x80x94 [where R6 is a hydrogen atom or a straight or branched chain C1-6 alkyl group]; and m is zero or an integer 1, 2 or 3.
When in the group -Alk(R5)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R5 may be present on any suitable carbon atom in -Alk. Where more than one R5 substituent is present these may be the same or different and may be present on the same or different atom in -Alk or in R5 as appropriate. Thus for example, -Alk(R5)m may represent a xe2x80x94CH(R5)2 group, such as a xe2x80x94CH(OH)Ar2 group where Ar2 is an aryl or heteroaryl group as defined below. Clearly, when m is zero and no substituent R5 is present the alkylene, alkenylene or alkynylene chain represented by Alk becomes an alkyl, alkenyl or alkynyl group.
When R5 is a substituted amino group it may be for example a group xe2x80x94NHR6 [where R6 is as defined above] or a group xe2x80x94N[R6]2 wherein each R6 group is the same or different.
When R5 is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R5 is a substituted hydroxyl or substituted thiol group it may be for example a group xe2x80x94OR6 or xe2x80x94SR6 respectively.
Esterified carboxyl groups represented by the group R5 include groups of formula xe2x80x94CO2Alk1 wherein Alk1 is a straight or branched, optionally substituted C1-8 alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C6-12arylC1-8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6-12aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-12aryloxyC1-8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1-8alkanoyloxyC1-8alkyl group, such as a pivaloyloxymethyl propionyloxyethyl or propionyloxypropyl group; or a C6-12aroyloxyC1-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group. Optional substituents present on the Alk1 group include R5 substituents described above.
When Alk is present in or as a substituent, it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, atoms or xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R7)xe2x80x94 groups.
Cycloalkyl groups represented by the group R5 include C5-7 cycloalkyl groups such as cyclopentyl or cyclohexyl groups.
Heterocycloalkyl groups represented by the group R5 include optionally substituted heteroC3-6heterocycloalkyl group containing one or two oxygen, sulphur or nitrogen containing groups as described above in relation to the group R3.
Aryl and heteroaryl groups represented by the groups R5, R6 or Ar2 include for example optionally substituted monocyclic or bicyclic C6-12 aromatic groups such as optionally substituted phenyl, 1- or 2-naphthyl groups, or optionally substituted monocyclic or bicyclic C1-9 heteroaromatic groups such as optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl and 5,6,7,8-tetrahydroisoquinolyl, purinyl, or pteridinyl groups. Optional substituents which may be present on these aromatic and heteroaromatic groups include those optional substituents described above in relation to the group R4, but excluding optionally substituted aromatic groups.
Particularly useful atoms or groups represented by R5, or Alk(R5)m as appropriate, include fluorine, chlorine, bromine or iodine atoms, or C1-6 alkyl, e.g. methyl or ethyl, C1-6 alkylamino, e.g. methylamino or ethylamino, C1-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, C1-6 alkylthiol e.g. methylthiol or ethylthiol, C1-6alkoxy, e.g. methoxy, ethoxy, n-propoxy or n-butoxy, C1-6haloalkoxy, e.g. trifluoromethoxy, C5-7cycloalkoxy, e.g. cyclopentyloxy, C1-6haloalkyl, e.g. trifluoromethyl, C1-6alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), C1-6aminoalkyl e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy or diethylaminoethoxy, imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido, 1,1,3-trioxo-benzo[d]thiazolidino, nitro, cyano, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk1 [where Alk1 is as defined above], C1-6 alkanoyl, e.g. acetyl, thiol (xe2x80x94SH), C1-6thioalkyl, e.g. thiomethyl or thioethyl, xe2x80x94SC(NH)NH2, phenoxy, sulphonyl (xe2x80x94SO3H), C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6 alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1-6dialkylamino-sulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6 dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, sulphonylamino (xe2x80x94NHSO2H), C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, e.g. 2-, 3- or 4-substituted phenylsulphonylamino such as 2-nitrophenylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonyl-amino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, phenylaminosulphonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino e.g. methylaminocarbonylamino or ethylaminocarbonyl-amino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, phenylaminocarbonylamino, C1-6alkanoylamino, e.g. acetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylamino-methyl, C1-6 alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxy-carbonylamino or t-butoxycarbonylamino, or optionally substituted heteroC3-6heterocycloalkyl, e.g. piperidinyl, piperazinyl, 3-methyl-1-piperazinyl, homopiperazinyl or morpholinyl groups.
Where desired, two R5 or -Alk(R5)m substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C1-6alkylenedioxy group such as methylenedioxy or ethylenedioxy.
It will be appreciated that where two or more R5 or -Alk(R5)m substituents are present, these need not necessarily be the same atoms and/or groups.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isethionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
It will be appreciated that depending on the nature of the group Ar and the substituents R2 and R3, the compounds of formula (1) may exist as geometrical isomers and/or may have one or more chiral centres so that enantiomers or diasteromers may exist. It is to be understood that the invention extends to all such isomers of the compounds of formula (1), and to mixtures thereof, including racemates.
One preferred class of compounds of formula (1) is that wherein the pyrimidine group is attached to the pyridyl group to yield a compound of formula (1a): 
and the salts, solvates, hydrates and N-oxides thereof.
Preferred compounds of this type are those of formula (1b): 
and the salts, solvates, hydrates and N-oxides thereof.
In the compounds of formulae (1), (1a) or (1b) R2 is preferably a hydrogen atom.
In the compounds according to the invention the aromatic group represented by Ar is preferably an optionally substituted phenyl group. The optional substituent(s) may be any of those R5 or -Alk(R5)m atoms or groups generally or particularly described above or in the Examples hereinafter. Particularly useful substituents include one, two or three R5 or -Alk(R5)m substituents present at any position in the phenyl ring, especially at the 3-, 4- and/or 5-positions relative to the carbon atom attached to the remainder of the compound of the invention.
In one particular preference, R3 in compounds of formulae (1), (1a) or (1b) is a piperazine or homopiperazine group, optionally substituted by one or two R4 substituents as described above. Preferably, the R3 piperazine or homopiperazine group is attached to the rest of the molecule of formula (1) through one of its nitrogen atoms. The piperazine or homopiperazine group is preferably disubstituted or is especially a monosubstituted group. When the piperazine or homopiperazine is monosubstituted and is attached to the remainder of the molecule of formula (1) through one of ifs nitrogen atoms then the substituent (R4) is preferably attached to the other free ring nitrogen atom. Especially useful R4 substituents are those particularly mentioned above and include for example optionally substituted C1-6alkyl, C1-6 alkoxy, xe2x80x94OHxe2x80x94, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94SO2NR1aR1b, or optionally substituted phenyl groups especially those groups of these types specifically described above or in the Examples hereinafter.
Preferred compounds according to the invention include the compounds specifically described in the Examples hereinafter.
Compounds according to the invention are potent and selective inhibitors of the protein tyrosine kinases ZAP-70 and syk, as demonstrated by differential inhibition of ZAP-70 and/or syk and other kinases such as cdc2 kinase, EGFr kinase, p56Ick kinase, protein kinase C, csk kinase and p59fyn kinase. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.
The compounds according to the invention are thus of particular use in the prophylaxis and treatment of disease in which inappropriate activation of ZAP-70 or syk plays a role. Such diseases include those in which inappropriate activation of T-cells, B-cells, mast cells or platelets is present or in which eosinophilia is a feature. Examples of these diseases include autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and psoriasis; graft v host disease and other transplantation associated rejection events; and allergic diseases such as asthma, atopic dermatitis, allergic rhinitis and allergic conjunctivitis. The compounds are also of use in the reduction of complications following percutaneous transluminal coronary angioplasty, in the prophylaxis and treatment of thrombosis of the major organs, deep vein thrombosis and peripheral vascular disease.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro-fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration and around 0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols Ar, R2, R3, R4, Alk, Alk1, Ar and Ar1 when used in the text or formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1991]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.
Thus according to a further aspect of the invention, a compound of formula (1) may be prepared by reaction of a guanidine of formula (2): 
or a salt thereof with an enaminone of formula (3):
R3COC(R2)CHN(R9)(R10)xe2x80x83xe2x80x83(3)
where R9 and R10, which may be the same or different is each a C1-6 alkyl group.
The reaction may be performed in a solvent, for example a protic solvent such as an alcohol, e.g. ethanol, methoxyethanol or propanol, optionally in the presence of a base e.g. an alkali metal base, such as sodium hydroxide or potassium carbonate, at an elevated temperature, e.g. the reflux temperature.
Salts of the compounds of formula (2) include acid salts such as inorganic acid salts e.g. hydrochlorides or nitrates.
Intermediate guanidines of formula (2) may be prepared by reaction of the corresponding amine ArNH2 with cyanamide at an elevated temperature. The reaction may be performed in a solvent such as ethanol at an elevated temperature, e.g. up to the reflux temperature. Where it is desired to obtain a salt of a guanidine of formula (2), the reaction may be performed in the presence of a concentrated acid, e.g. hydrochloric or nitric acid.
The amines ArNH2 are either known compounds or may be obtained by conventional procedures, for example by hydrogenation of the corresponding nitro derivatives using for example hydrogen in the presence of a metal catalyst in a suitable solvent, for example as more particularly described in the interconversion reactions discussed below. The nitrobenzenes for this particular reaction are either known compounds or may be prepared using similar methods to those used for the preparation of the known compounds.
Intermediate enaminones of formula (3) are either known compounds or may be prepared by reaction of an acetyl derivative R3COCH2R2 with an acetal (R9)(R1)NCH(OCH3)2 at an elevated temperature. The starting materials for this reaction are either known compounds of may be prepared by methods analogous to those used for the preparation of the known compounds.
In another process according to the invention, a compound of formula (1) may be prepared by displacement of a leaving atom or group in a pyrimidine of formula (4): 
[where L is a leaving atom or group], with an amine ArNH2.
The reaction may be performed at an elevated temperature, for example the reflux temperature, where necessary in the presence of a solvent, for example an alcohol, such as 2-ethoxyethanol or an aromatic hydrocarbon such as toluene or mesitylene optionally in the presence of a base for example an amine such as pyridine. Where desired, the reaction may also be performed on an intermediate of formula (4) which is linked, for example via its R3 group, to a solid support, such as a polystyrene resin. After the reaction, the desired compound of formula (1) may be displaced from the support by any convenient method, depending on the original linkage chosen. Particular examples of such solid-phase syntheses are given in the Examples hereinafter.
Particular examples of leaving atoms or groups represented by L in compounds of formula (4) include halogen atoms such as a chlorine or bromine atom, and sulphonyloxy groups, for example alkylsulphonyloxy groups such as a methylsulphonyloxy group.
Intermediate pyrimidines of formula (4) may be prepared by cross-coupling a pyrimidine of formula (5): 
[where Hal is a halogen atom] with a pyridine of formula (6): 
[where Hal1 is a halogen atom such as a chlorine atom, and M is a metal atom, such as a zinc atom].
The reaction may be carried out in the presence of a metal catalyst, for example a metal complex catalyst such as a palladium complex, e.g. tetrakis(triphenylphosphine)palladium, in a solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, at an elevated temperature, e.g. the reflux temperature.
Intermediates of formula (6) may be prepared by conventional procedures, for example, where M is a zinc atom, by reaction of a halide of formula (7): 
[where Hal2 is for example a bromine atom)] with tert-butyllithium at a low temperature e.g. around xe2x88x92100xc2x0 C. followed by reaction with a zinc salt, e.g. zinc chloride at a low temperature, e.g. around xe2x88x9275xc2x0 C. Both reactions may be carried out in a solvent such as an ether, e.g. tetrahydrofuran. Any reactive groups in R3 not involved in this or the above-described coupling reaction may need to be in a protected form, the protecting group being removed prior to, during or subsequent to the displacement reaction involving the pyrimidines of formula (4).
The halide starting materials of formula (7) may be prepared by displacement of a leaving group from a pyridine of formula (8): 
(where L is a leaving group as described above] using a nucleophilic reagent R3H. The reaction may be performed as described above in relation to the preparation of compounds of formula (1) from the intermediate pyrimidines of formula (4).
Intermediates of formulae (5) and (8) are either known compounds or may be prepared using methods analogous to those used for the preparation of the known compounds.
In another example of a displacement reaction according to the invention a compound of formula (1) wherein R3 is an optionally substituted heterocycloalkyl group containing a ring nitrogen atom attached to the remainder of the molecule of formula (1), may be prepared by reaction of a pyrimidine of formula (9): 
[where L is a leaving group as previously described], with a heterocyclic amine R3aNH [where R3aN is an optionally substituted heterocycloalkyl group R3 containing at least one nitrogen atom.]
The reaction may be performed as described above in relation to the preparation of compounds of formula (1) from the intermediate pyrimidines of formula (4). The intermediate amines R3aNH are either known compounds or may be prepared from known compounds for example by the simple interconversion reactions described for the groups Ar and/or R3 in the text or Examples hereinafter.
The intermediate pyrimidines of formula (9) may be prepared from the corresponding guanidine of formula (2) and an enaminone of formula (10): 
using the conditions described above for the reaction of intermediates of formulae (2) and (3). The enaminones of formula (10) may be prepared using an appropriate acetyl derivative of formula (11): 
with an acetal (R9)(R10)NCH(OCH3)2 as described previously for the preparation of enaminones of formula (3).
Compounds of formula (1) may also be prepared by interconversion of other compounds of formula (1) and it is to be understood that the invention extends to such interconversion processes. Thus, for example, standard substitution approaches employing for example alkylation, arylation, heteroarylation, acylation, thioacylation, sulphonylation, formylation or coupling reactions may be used to add new substitutents to and/or extend existing substituents in compounds of formula (1). Alternatively existing substituents in compounds of formula (1) may be modified by for example oxidation, reduction or cleavage reactions to yield other compounds of formula (1).
The following describes in general terms a number of approaches which can be employed to modify existing Ar and/or R3 groups in compounds of formula (1). It will be appreciated that each of these reactions will only be possible where an appropriate functional group exists in a compound of formula (1).
Thus, for example alkylation, arylation or heteroarylation of a compound of formula (1) may be achieved by reaction of the compound with a reagent R4L, AlkL, Ar1 L or Ar2L where L is a leaving atom or group as described above. The reaction may be carried out in the presence of a base, e.g. an inorganic base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran, at around 0xc2x0 C. to around 40xc2x0 C.
In a variation of this process the leaving group L may be alternatively part of the compound of formula (1) and the reaction performed with an appropriate nucleophilic reagent at an elevated temperature. Where appropriate the reaction may be performed in a solvent such as an alcohol, e.g. ethanol.
In another general example of an interconversion process, a compound of formula (1) may be acylated or thioacylated. The reaction may be performed for example with an acyl halide or anhydride in the presence of a base, such as a tertiary amine e.g. triethylamine in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at for example ambient temperature, or by reaction with a thioester in an inert solvent such as tetrahydrofuran at a low temperature such as around 0xc2x0 C. The reaction is particularly suitable for use with compounds of formula (1) containing primary or secondary amino groups.
In a further general example of an interconversion process, a compound of formula (1) may be formylated, for example by reaction of the compound with a mixed anhydride HCOOCOCH3 or with a mixture of formic acid and acetic anhydride.
Compounds of formula (1) may be prepared in another general interconversion reaction by sulphonylation, for example by reaction of a compound of formula (1) with a reagent AlkS(O)2L, or Ar1S(O)2L in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature. The reaction may in particular be performed with compounds of formula (1) possessing a primary or secondary amino group.
In another example, a compound of formula (1) may be prepared by sulphamoylation, for example by reaction of a compound of formula (1) where, for example R3 contains an available nitrogen atom, with a reagent R1aR1bNSO2L in the presence of a solvent, e.g. an organic amine such as triethylamine at around ambient temperature.
In further examples of interconversion reactions according to the invention compounds of formula (1) may be prepared from other compounds of formula (1) by modification of existing functional groups in the latter.
Thus in one example, ester groups xe2x80x94CO2Alk1 in compounds of formula (1) may be converted to the corresponding acid [xe2x80x94CO2H] by acid- or base-catalysed hydrolysis or by catalytic hydrogenation depending on the nature of the group Alk1. Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol. Catalytic hydrogenation may be carried out using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol, e.g. methanol.
In a second example, xe2x80x94OAlk2 [where Alk2 represents an alkyl group such as a methyl group] groups in compounds of formula (1) may be cleaved to the corresponding alcohol xe2x80x94OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around xe2x88x9278xc2x0 C.
In another example, alcohol xe2x80x94OH groups in compounds of formula (1) may be converted to a corresponding xe2x80x94OAlk or xe2x80x94OAr group by coupling with a reagent AlkOH or AROH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
Aminosulphonylamino [xe2x80x94NHSO2NH2] groups in compounds of formula (1) may be obtained, in another example, by reaction of a corresponding amine [xe2x80x94NH2] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In a further example, amine [xe2x80x94NH2] groups in compounds of formula (1) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [xe2x80x94NO2] group may be reduced to an amine [xe2x80x94NH2], for example by catalytic hydrogenation as just described, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70xc2x0 C. to 80xc2x0 C., or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Where salts of compounds of formula (1) are desired, these may be prepared by conventional means, for example by reaction of a compound of formula (1) with an appropriate acid or base in a suitable solvent or mixture of solvents, e.g. an organic solvent such as an ether, e.g. diethylether, or an alcohol, e.g. ethanol.